Σύγκριση της επίδρασης χορήγησης νεμπιβολόλης ή νεμπιβολόλης

O R I G I N A L
P A P E R
Ε Ρ Ε Υ Ν Η Τ Ι Κ Η
Hellenic Journal of Atherosclerosis 5(2):131–138
Ε Ρ Γ Α Σ Ι Α
Ελληνική Επιθεώρηση Αθηροσκλήρωσης 5(2):131–138
Effect of nebivolol
or nebivolol/
hydrochlorothiazide
plus atorvastatin
on glycemic profile
in patients
with hypertension
and dyslipidemia
E. Moutzouri, A. Kei,
E. Liberopoulos, M. Elisaf
Σύγκριση της επίδρασης
χορήγησης νεμπιβολόλης
ή νεμπιβολόλης/
υδροχλωροθειαζίδης
μαζί με ατορβαστατίνη
στο γλυκαιμικό προφίλ
ασθενών με αρτηριακή
υπέρταση
και δυσλιπιδαιμία
Ε. Μουτζούρη, Α. Κεή,
Ε. Λυμπερόπουλος, Μ. Ελισάφ
Department of Internal Medicine, Medical School,
University of Ioannina, Ioannina, Greece
Τομέας Παθολογίας, Ιατρική Σχολή,
Πανεπιστήμιο Ιωαννίνων, Ιωάννινα
AIM: A potentially diabetogenic role for statins has been
suggested. Similarly, first and second generation betablockers and hydrochlorothiazide (HCTZ) have negative effects on glucose homeostasis. Nebivolol is a third
generation beta-blocker which may beneficially affect
carbohydrate metabolism. The effect of combined treatment with nebivolol, HCTZ and atorvastatin is unknown.
MATERIAL-METHODS: This is a prospective, randomized, open-label, blinded endpoint (PROBE) study.
Drug-naive patients with hypertension and dyslipidemia
were recruited. All patients received atorvastatin (10
mg). In addition, patients with stage 1 hypertension received nebivolol (5 mg, AN group), while patients with
stage 2 hypertension received nebivolol/HCTZ (5/12.5
mg, AN/H-12.5 group or 5/25 mg, AN/H-25 group).
ΣΚΟΠΟΣ: Τελευταία γίνεται μεγάλη συζήτηση σχετικά
με την αρνητική επίδραση που ενδεχομένως ασκούν οι
στατίνες και τα αντιυπερτασικά φάρμακα στην ομοιοστασία των υδατανθράκων. Συγκεκριμένα, τόσο η ατορβαστατίνη όσο και τα θειαζιδικά διουρητικά και οι βαποκλειστές ασκούν δυσμενή επίδραση στο γλυκαιμικό
προφίλ. Η νεμπιβολόλη, σε αντίθεση με τους κλασικούς
β-αποκλειστές, έχει συσχετισθεί με βελτίωση της ομοιοστασίας των υδατανθράκων. Ωστόσο, η επίδραση της
συγχορήγησης ατορβαστατίνης-νεμπιβολόλης με ή χωρίς υδροχλωροθειαζίδη στον μεταβολισμό των υδατανθράκων παραμένει άγνωστη.
ΥΛΙΚΟ-ΜΕΘΟΔΟΣ: Στρατολογήθηκαν ασθενείς με
αρτηριακή υπέρταση και δυσλιπιδαιμία που δεν είχαν
λάβει καμία αντιυπερτασική ή υπολιπιδαιμική αγωγή
Η παρούσα μελέτη πραγματοποιήθηκε με υποτροφία
από την Ελληνική Εταιρεία Μελέτης της Υπέρτασης
Evangelos N. Liberopoulos
Department of Internal Medicine, Μedical School,
University of Ioannina, GR-451 10 Ioannina, Greece
Tel: (+30) 2651 0 07502, Fax: (+30) 2651 0 07016
e-mail: vaglimp@yahoo.com
© 2014 Ελληνική Εταιρεία Αθηροσκλήρωσης
Ευάγγελος Ν. Λυμπερόπουλος
Tομέας Παθολογίας, Ιατρική Σχολή,
Πανεπιστήμιο Ιωαννίνων, 451 10 Ιωάννινα
Τηλ: 2651 0 07502, Fax: 2651 0 07016
e-mail: vaglimp@yahoo.com
132
The primary efficacy endpoint was the between group
mean change from baseline in homeostasis model assessment of insulin resistance (HOMA-IR) index at 12
weeks. RESULTS: Seventy-eight patients completed
the study. In both AN and AN/H-12.5 group HOMA-IR
levels did not significantly change [from 1.6 (1.4–2.1)
to 1.5 (1.4–2.0, P=NS) compared with baseline and
from 1.6 (1.3–2.2) to 1.7 (1.7–2.4), P=0.07 compared
with baseline), respectively]. In contrast, the HOMA-IR
significantly increased by 10% in the AN/H-25 group
[from 1.7 (1.3–2.3) to 1.9 (1.4–2.4), P=0.02 compared
with baseline and P<0.01 for the comparison with the
other 2 groups]. CONCLUSIONS: Administration of
nebivolol may counterbalance the negative effects on
HOMA-IR of atorvastatin with or without HCTZ 12.5
mg but not that of atorvastatin plus HCTZ 25 mg.
E. Moutzouri et al
για τουλάχιστον 6 εβδομάδες πριν από τη συμμετοχή
τους στη μελέτη. Όλοι οι συμμετέχοντες έλαβαν ατορβαστατίνη (10 mg) και επιπρόσθετα οι ασθενείς με υπέρταση σταδίου 1 έλαβαν νεμπιβολόλη (5 mg, ομάδα
ΑΝ), ενώ οι ασθενείς με υπέρταση σταδίου 2 έλαβαν
συνδυασμό νεμπιβολόλης/υδροχλωροθειαζίδης (5/12,5
mg, ομάδα ΑΝ/Υ-12,5 ή 5/25 mg, ομάδα ΑΝ/Υ-25). Το
πρωτογενές καταληκτικό σημείο ήταν η μεταβολή του
δείκτη αντίστασης στην ινσουλίνη HOMA-IR 3 μήνες
μετά την έναρξη της θεραπείας. ΑΠΟΤΕΛΕΣΜΑΤΑ:
Εβδομήντα οκτώ ασθενείς ολοκλήρωσαν τη μελέτη.
Τόσο στην ομάδα ΑΝ όσο και στην ομάδα ΑΝ/Υ-12,5
δεν παρατηρήθηκε σημαντική μεταβολή των επιπέδων
του HOMA-IR [από 1,6 (1,4–2,1) σε 1,5 (1,4–2,0) και
από 1,6 (1,3–2,2) σε 1,7 (1,7–2,4), αντίστοιχα, P=NS
σε σύγκριση με τα αρχικά επίπεδα], ενώ στην ομάδα
ΑΝ/Υ-25 που παρατηρήθηκε αύξηση κατά 10% [από
1,7 (1,3–2,3) σε 1,9 (1,4–2,4), P=0,02 σε σύγκριση με
τα αρχικά επίπεδα και P<0,01 για όλες τις συγκρίσεις
μεταξύ των ομάδων]. ΣΥΜΠΕΡΑΣΜΑΤΑ: Η χορήγηση
νεμπιβολόλης φαίνεται να αντιρροπεί τη δυσμενή επίδραση της ατορβαστατίνης με ή χωρίς 12,5 mg υδροχλωροθειαζίδης στα επίπεδα του HOMA-IR αλλά όχι και της
ατορβαστατίνης με 25 mg υδροχλωροθειαζίδης.
Key words: Atorvastatin, glucose, HOMA-IR, insulin,
nebivolol, hydrochlorothiazide.
Λέξεις ευρετηρίου: Aτορβαστατίνη, γλυκόζη, HOMA-IR,
ινσουλίνη, νεμπιβολόλη, υδροχλωροθειαζίδη.
1. Introduction
has been associated with a beneficial effect on glucose
metabolism and may ameliorate the negative effect of
HCTZ in hypertensive patients.10 The possible effects of
combined treatment with atorvastatin plus nebivolol
with or without HCTZ on carbohydrate metabolism remain unknown.
Diabetes is a worldwide health problem with epidemic proportions which may lead to functional disability, vascular complications and premature death.
Thus, the prevention or delay of diabetes development is of major clinical importance.1,2 Hypertension is
considered as a risk factor for new onset diabetes and
hypertensive patients usually receive a statin in addition to antihypertensive drugs. 3 However, a possible
diabetogenic role for statins has been suggested both
from large trials and meta-analyses.4 Several statins
have been shown to increase insulin resistance indices,
glucose levels and glycosylated hemoglobin (HbA1c). 5,6
Moreover, both first and second generation betablockers and hydrochlorothiazide (HCTZ), the most
commonly used diuretic, have been associated with
negative effects on glucose profile.7,8 The combination
of a beta-blocker plus HCTZ is associated with the most
pronounced increase in new diabetes.9 On the contrary,
nebivolol, a third generation b1 selective beta-blocker,
© 2014 Ελληνική Εταιρεία Αθηροσκλήρωσης
The aim of the present study was to evaluate the effect of nebivolol or nebivolol/HCTZ plus atorvastatin
on glycemic profile in patients with hypertension and
dyslipidemia. The primary endpoint was the between
group difference in mean change from baseline in
HOMA-IR index at 12 weeks.
2. Patients-method
This was a prospective, randomized, open-label,
blinded endpoint (PROBE) study. Consecutive subjects
with dyslipidemia and hypertension attending the
Outpatient Lipid and Obesity Clinic of the University
Hospital of Ioannina, Ioannina, Greece were recruited.
133
NEBIVOLOL ΑΝD INSULIN RESISTANCE
Eligible patients were hypertensive drug-naive subjects
with low density lipoprotein cholesterol (LDL-C) levels
above those recommended by the European Society of
Cardiology and the European Atherosclerosis Society
(ESC/EAS) based on each patient risk score.11 Diagnosis
of hypertension was based on abnormally high blood
pressure (BP) measurements of ≥2 properly measured,
seated blood pressure (BP) readings on each of 2 or
more outpatient visits.
Subjects with: (i) history of ischemic heart disease
or any other vascular disease, (ii) impaired hepatic
function [aspartate and/alanine aminotransferase
(AST and/or ALT) >2x the upper normal limit and/or
history of chronic liver disease, such as cirrhosis], (iii)
alcohol abuse, (iv) impaired renal function (serum
creatinine >1.6 mg/dL), (v) diabetes [present if a subject was treated for diabetes or by 2 separate fasting plasma glucose (FPG) measurements ≥126 mg/
dL], (vi) severe hypertriglyceridemia [triglyceride (TG)
levels >500 mg/dL], (vii) thyroid dysfunction [thyroid
stimulating hormone (TSH) levels >5.0 μU/L], and
(viii) patients who received hypolipidemic or antihypertensive drugs in the last 3 months prior to recruitment were excluded.
All patients were given atorvastatin 10 mg/day. In
addition, patients with stage 1 hypertension were prescribed nebivolol 5 mg/day (AN group), while patients
with stage 2 hypertension were randomized to fixed
combination of nebivolol 5 mg/day plus HCTZ 12.5
mg/day (AN-H/12.5 group) or nebivolol 5 mg/day plus
HCTZ 25 mg/day (AN-H/25).
The primary endpoint was the between group difference in mean change from baseline in HOMA-IR index
at 12 weeks. Secondary efficacy endpoints included
changes in FPG and HbA1c levels, blood pressure, heart
rate and lipid profile.
All patients were given similar dietary advice. Compliance with treatment and lifestyle habits was assessed by questionnaire and tablet count. All study participants gave their written informed consent prior to
enrolment, and the Ethics Committee of the University
Hospital of Ioannina approved the study protocol.
3. Laboratory measurements
Visits took place at baseline and 12 weeks after the
start of treatment. At each visit, BP was measured in
triplicate in the right arm after patients had rested
for 10 minutes in a sitting position. Measurements
were performed by trained clinicians using an electronic sphygmomanometer (WatchBP Office, Microlife
WatchBP AG,Widnau, Switzerland). Blood samples for
laboratory tests were obtained after a 12 h overnight
fast. Serum levels of FPG, total cholesterol (TC), high
density lipoprotein cholesterol (HDL-C), and TG were
determined enzymatically in the laboratory of the
University Hospital of Ioannina using an Olympus AU
600 analyzer (Olympus Diagnostica GmbH, Hamburg,
Germany). Intra-assay and total coefficient variations
for glucose assay were 0.7% and 1.6%, respectively.
LDL-C was calculated using the Friedewald equation
[provided that TGs were <350 mg/dL (3.95 mmol/L)].
The determination of HbA1c (expressed as percentage of the total hemoglobin concentration) was based
on a latex agglutination inhibition assay (Randox
Laboratories Ltd., Crumlin, United Kingdom). HbA1c
values are expressed as percentage of the total hemoglobin concentration. The sensitivity of the assay
is 0.25 g/dL of HbA1c and the within -and betweenrun precision is <6.67% and <4.82%, respectively.
Fasting serum insulin was measured by an AxSYM insulin assay microparticle enzyme immunoassay on an
AzSYM analyzer (Abbott Diagnostics, Illinois, United
States). Intra-assay and total coefficient variations for
insulin assay were 4.1% and 5.3%, respectively. The
HOMA-IR index was calculated as follows: HOMA-IR
index=fasting insulin (mU/L)×FPG (mg/dL)/405. All laboratory determinations were performed blindly with
regard to treatment allocation.
4. Statistics
We calculated that a sample size of 75 will give a 90%
power to detect a significant difference in HOMA-IR
change between groups. Values are given as mean±SD
and median (range) for parametric and non-parametric
data, respectively. Continuous variables were tested
for lack of normality by the Kolmogorov-Smirnov test,
and logarithmic transformations were accordingly performed for nonparametric variables. The paired-sample
t-test was used for assessing the effect of treatment in
each group. Analysis of covariance (ANCOVA), adjusted
for baseline values, was used for comparisons between
groups. All reported p values are based on two-sided
tests with a significance level of 0.05. Analyses were
performed using the Statistical Package for the SPSS
15.0 (SPSS Inc, Chicago, IL).
© 2014 Ελληνική Εταιρεία Αθηροσκλήρωσης
134
5. Results
Recruitment took place from September 2012 to
October 2013 and follow up ended in January 2014.
Seventy-eight (42 men, 59±11 years) patients were
enrolled and completed the study (n=32, 26 and 20
in the AN, AN/H-12.5 and AN/H-25 group, respectively). Except for BP values, no significant differences
in baseline data were found across groups regarding
demographic characteristics and serum metabolic
parameters (table 1). Compliance rate was >80% in
all participants. No changes in body weight, dietary
habits (including salt intake), or medications were reported during the follow up.
6. Effect on glycemic profile
In both AN and AN/H-12.5 group HOMA-IR levels did
not significantly change, while in the AN/H-25 HOMAIR increased by 10% (P=0.02 compared with baseline
and P<0.01 for comparisons with the other 2 groups).
FPG levels did not significantly change in the AN group
and in the AN/H-12.5 group, while they increased by 7%
in the AN/H-25 group (P=0.01 compared with baseline
and P<0.01 for comparisons with the other 2 groups).
Both AN and AN/H-12.5 groups were not associated
with significant changes in HbA1c levels, while in the
AN/H-25 group HbA1c levels increased by 0.3% (P=0.03
E. Moutzouri et al
compared with baseline and P=0.01 compared with the
other 2 groups) (table 2).
7. Effect on lipid profile
Total cholesterol and LDL-C levels decreased similarly
in all treatment groups (P<0.01 compared with baseline
in all groups). Triglyceride and HDL-C levels did not significantly change in any group (table 3).
8. Effect on BP levels and heart rate
Systolic BP decreased by 7 mmHg in the AN group
(P<0.01 compared with baseline), while a greater reduction was reported in the AN/H-12.5 and AN/H-25 groups
(by 11 and 12 mmHg, respectively, P<0.01 compared
with baseline). Diastolic BP decreased by 7, 10 and 12
mmHg in the AN, AN/H-12.5 and AN/H-25 groups, respectively (P<0.01 compared with baseline). Heart rate
decreased similarly in all treatment groups (by 6%, 5%
and 5% in the AN, AN/H-12.5 and AN/H-25, respectively,
P<0.01 compared with baseline) (table 3).
9. Discussion
To our best of knowledge this is the first study
evaluating the effect of combined administration of a
statin plus beta blocker with or without a diuretic on
Table 1. Baseline characteristics of patients who completed the study* (N = 78)
AN
AN/H-12.5
N (males/females)
32 (17/15)
26 (14/12)
Age, years
61±10
58±14
SBP, mmHg
148±5
165±5
DBP, mmHg
96±3
103±3
HR, bpm
80±4
79±5
Metabolic syndrome (%)
17 (53)
15 (58)
Smoking (%)
10 (31)
9 (35)
HOMA-IR
1.6 (1.4–2.1)
1.6 (1.3–2.2)
FPG, mg/dL (mmol/L)
94±7 (5.2±0.4)
95±7 (5.3±0.4)
HbA1c (%)
5.4±0.5
5.5±0.4
29.1±2.5
29.1±3.1
BMI, kg/m2
TC, mg/dL (mmol/L)
224±22 (5.8±0.6)
220±17 (5.7±0.4)
Triglycerides, mg/dL [mmol/L]
117 (89–159) [1.3 (1.0–1.8)] 123 (88–160) [1.4 (0.9–1.8)]
HDL-C, mg/dL (mmol/L)
48±5 (1.2±0.1)
49±7 (1.3±0.2)
LDL-C, mg/dL (mmol/L)
153±12 (3.9±0.3)
146±15 (3.8±0.4)
AN/H-25
20 (11/9)
59±12
167±5
105±4
82±3
11 (55)
7 (35)
1.7 (1.3–2.3)
94±6 (5.2±0.3)
5.3±0.5
28.8±3.2
225±21 (5.8±0.5)
118 (90–150) [1.3 (1.0–1.7)]
47±6 (1.2±0.2)
154±14 (3.9±0.4)
P
NS
NS
0.01
0.01
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
AN: atorvastatin-nebivolol group, AN/H-12.5: atorvastatin-nebivolol-hydrochlorothiazide 12.5 mg group, AN/H-25: atorvastatin-nebivolol-hydrochlorothiazide 25 mg group, NS: non-significant, BMI: body mass index, HOMA-IR: homeostasis model assessment of insulin resistance index, FPG:
fasting plasma glucose, HbA1c: glycosylated hemoglobin, TC: total cholesterol, HDL-C: high-density lipoprotein cholesterol, LDL-C: low-density
lipoprotein cholesterol, SBP: systolic blood pressure, DBP: diastolic blood pressure, HR: heart rate
*Values are expressed as mean ± standard deviation [except for triglycerides which are expressed as median (range)]
© 2014 Ελληνική Εταιρεία Αθηροσκλήρωσης
135
NEBIVOLOL ΑΝD INSULIN RESISTANCE
Table 2. Glycemic profile at baseline and 3 months after treatment.*
HOMA-IR
AN
AN/H-12.5
AN/H-25
FPG, mg/dL (mmol/L)
AN
AN/H-12.5
AN/H-25
HbA1c (%)
AN
AN/H-12.5
AN/H-25
Baseline
3 months
Percentage change (%)
1.6 (1.4–2.1)
1.6 (1.3–2.2)
1.7 (1.3–2.3)
1.5 (1.4–2.0)
1.7 (1.7–2.4)
1.9 (1.4–2.4)
–6
+6
+10i–iii
94±7 (5.2±0.4)
95±7 (5.3±0.4)
94±6 (5.2±0.3)
95±6 (5.3±0.3)
99±7 (5.5±0.4)
101±7 (5.6±0.4)
+1
+4
+7i–iii
5.4±0.5
5.5±0.4
5.3±0.5
5.5±0.4
5.6±0.3
5.6±0.4
+0.1
+0.1
+0.3i–iii
HOMA-IR: homeostasis model assessment of insulin resistance index, FPG: fasting plasma glucose, AN: atorvastatin-nebivolol group, AN/H-12.5:
atorvastatin-nebivolol-hydrochlorothiazide 12.5 mg group, AN/H-25: atorvastatin-nebivolol-hydrochlorothiazide 25 mg group, HbA1c: glycosylated hemoglobin
*Values are expressed as mean ± standard deviation [except for HOMA-IR index which is expressed as median (range)]
(i) p<0.05 versus baseline, (ii) p<0.05 versus AN, (iii) p <0.05 versus AN/H-12.5 group
Table 3. Lipid profile, blood pressure and heart rate at baseline and 3 months after treatment.*
Baseline value
3 months
change (%)
224±22 (5.8±0.6)
220±17 (5.7±0.4)
225±21 (5.8±0.5)
160±15 (4.1±0.4)
162±18 (4.2±0.5)
160±19 (4.1±0.5)
–29i
–26i
–29i
117 (89–159) [1.3 (1.0–1.8)]
123 (88–160) [1.4 (0.9–1.8)]
118 (90–150) [1.3 (1.0–1.7)]
107 (83–148) [1.2 (0.9–1.7)]
115 (80–150) [1.30 (0.9–1.7)]
110 (85–145) [1.2 (1.0–1.6)]
–9
–7
–7
HDL-C, mg/L (mmol/L)
AN
AN/H-12.5
AN/H-25
48±5 (1.2±0.1)
49±7 (1.3±0.2)
47±6 (1.2±0.2)
50±6 (1.3±0.2)
50±4 (1.3±0.1)
46±5 (1.2±0.1)
+4
+2
–2
LDL-C, mg/L (mmol/L)
AN
AN/H-12.5
AN/H-25
153±12 (3.9±0.3)
146±15 (3.8±0.4)
154±14 (3.9±0.4)
95±13 (2.5±0.3)
89±14 (2.3±0.4)
92±15 (2.4±0.4)
–38i
–39i
–40i
SBP, mmHg
AN
AN/H-12.5
AN/H-25
148±5
165±5
167±5
138±6
149±5
147±7
–7i
–11i,ii
–12i,ii
DBP, mmHg
AN
AN/H-12.5
AN/H-25
96±3
103±3
105±4
89±4
93±3
92±5
–7i
–10i,ii
–12i,ii
HR, bpm
AN
AN/H-12.5
AN/H-25
80±4
79±5
82±3
75±3
75±4
78±4
–6i
–5i
–5i
TC, mg/L (mmol/L)
AN
AN/H-12.5
AN/H-25
Triglycerides, mg/L [mmol/L]
AN
AN/H-12.5
AN/H-25
TC: total cholesterol, AN: atorvastatin-nebivolol group, AN/H-12.5: atorvastatin-nebivolol-hydrochlorothiazide 12.5 mg group, AN/H-25: atorvastatin-nebivolol-hydrochlorothiazide 25 mg group, HDL-C: high-density lipoprotein cholesterol, LDL-C: low-density lipoprotein cholesterol, SBP:
systolic blood pressure, DBP: diastolic blood pressure, HR: heart rate
*Values are expressed as mean±standard deviation [except for triglycerides which are expressed as median (range)].
(i) P<0.05 versus baseline, (ii) P<0.05 versus AN
© 2014 Ελληνική Εταιρεία Αθηροσκλήρωσης
136
glycemic profile in patients with dyslipidemia and hypertension. Both AN and AN/H-12.5 groups were not
associated with significant HOMA-IR index change,
while HOMA-IR significantly increased in AN/H-25
group. Similarly, HbA1c and FPG level increased in
AN/H-25 group, while it did not change in the other 2
treatment groups.
In the reanalysis of data from Nateglinide and
Valsartan in Impaired Glucose Tolerance Outcomes
Research (NAVIGATOR) trial diuretics and statins were
associated with increased risk of new onset diabetes,
whereas the effect beta-blockers was non-significant
in patients with impaired glucose tolerance and other
cardiovascular risk factors.12 Atorvastatin has been
associated with increased insulin resistance, HOMAIR index and HbA1c levels in both diabetic and nondiabetic patients.13–15 Similarly, HCTZ has been associated with negative effects on glycemic profile. 8
Contrary to the first and second generation betablockers, nebivolol has been associated with beneficial effects on glucose metabolism in a number of
studies.16–19 In a previous study nebivolol (5 mg/day)
lacked detrimental metabolic effect, while metoprolol
(100 mg/day) decreased insulin sensitivity in patients
with metabolic syndrome.16 In another study, nebivolol (5 mg/day), in contrast to metoprolol (100 mg/day),
improved oxidative stress and insulin sensitivity in
hypertensive patients.18 In hypertensive patients with
impaired glucose tolerance insulin sensitivity was
not modified by nebivolol (2.5–5 mg/day), while atenolol (50–100 mg/day) reduced insulin sensitivity.17
In another study, hypertensive patients first received
nebivolol and after 1 month, in those patients whose
BP was not normalized HCTZ was added.10 Nebivolol
(5 mg/day) reduced HOMA-IR index but the adjunct
of HCTZ (both at 12.5 and 25 mg/day) blunted this reduction.10
Nebivolol has been shown to increase the bioavailability of endogenous nitric oxide (NO).19 As NO improves insulin sensitivity and muscle glucose uptake,
this may contribute to the favorable effect of nebivolol on insulin sensitivity. 20 Moreover, nebivolol has
been associated with increased adiponectin levels
in hypertensive patients.18 Of note, adiponectin has
been associated with novel insulin-sensitizing properties. 21 The mechanism traditionally associated with
this increased risk of diuretic-associated diabetes
mellitus is a reduction in serum potassium. A metaanalysis of 59 studies found a significant correlation
between the degree of diuretic-induced hypokalemia
© 2014 Ελληνική Εταιρεία Αθηροσκλήρωσης
E. Moutzouri et al
and an increase in plasma glucose. 22 Moreover, there is
evidence that prevention of hypokalemia with potassium supplementation or potassium-sparing agents
lessens the degree to which FPG is increased. 22 The
mechanisms by which statins may adversely affect
glucose homeostasis are not fully understood. Statins
by inhibiting mevalonate pathway block the synthesis not only of cholesterol, but also of several mevalonate products known as isoprenoids.4 Isoprenoids,
including farsenyl pyrophosphate, geranylgeranyl pyrophosphate and ubiquinone, are known to enhance
glucose uptake by upregulating the membrane transporter protein glucose transporter 4, which plays a
key role in glucose uptake by adipocytes.4 Therefore,
statin-induced inhibition of isoprenoid synthesis may
increase insulin resistance in the adipose tissue and
induce hyperinsulinemia. Most potent statins in terms
of inhibiting mevalonate pathway, such as atorvastatin, as well as higher doses of statin treatment may
exert a more profound impact on insulin resistance
compared with conventional statins at low dosage
regimens. Last, statins may exert a deleterious effect
on insulin secretion by pancreatic islets.4
As in treated hypertensive subjects, the occurrence
of new diabetes portends a risk for subsequent cardiovascular disease similar to that of previously known
diabetes, the raising critical question is whether our
study’s results translate into reduced new-onset diabetes and cardiovascular disease incidence. 23 Insulin
resistance, HOMA-IR and FPG levels are independent
predictors of incident diabetes. 24 Moreover, in both
non diabetic and diabetic subjects, HOMA-IR index
is an independent predictor of cardiovascular disease. 25–26 Thus, insulin resistance might be regarded
as an accomplice in the pathogenesis of cardiovascular disease. Nevertheless, it is interesting to establish
whether HOMA-IR reduction decreases cardiovascular
disease risk. This information would be of great clinical value, because it might strongly justify and encourage the use of drugs capable of improving insulin
sensitivity, such as nebivolol, with the aim of reducing
cardiovascular risk. In this context, it is important to
remember that physical activity, which improves insulin sensitivity, was shown to prevent cardiovascular
disease in patients with type 2 diabetes. 27 Moreover,
administration of metformin, a drug that effectively
reduces HOMA-IR index, was the only therapeutic approach associated with reduced incidence of myocardial infarction in the UK Prospective Diabetes Study. 28
Specifically designed studies should address the treat-
NEBIVOLOL ΑΝD INSULIN RESISTANCE
ment-induced HOMA-IR index modulation in terms of
cardiovascular risk.
It has to be underlined that the BP lowering effects
of both add-on 12.5 and 25 mg of HCTZ were almost
identical, but only the higher dose adversely affected
glucose metabolism compared with nebivolol monotherapy. Thus, as it is stated in the recent guidelines,
the administration of 12.5 mg of HCTZ may be recommended. 3 What is more, contrary to previous studies,
the addition of HCTZ did not adversely affect lipid profile, regardless of the dose.8
10. Study limitations and strengths
A major limitation of our study is the open-label design and the lack of monotherapy groups. However, it
was considered unethical to leave these high-risk patients without combined antihypertensive and hypolipidemic treatment.
On the other hand, it was an adequately powered
randomized study with all laboratory determinations
being performed blindly to treatment allocation. Also,
study design is relevant to everyday clinical practice.
11. Conclusions
Administration of nebivolol may ameliorate the possible negative effects of atorvastatin with or without
HCTZ 12.5 mg but not that of atorvastatin plus dose of
HCTZ 25 mg on glucose metabolism.
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Submited date 20/02/2014
Accepted date 28/02/2014

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